Papa, J. L. | Search bioRxiv

bioRxiv2025

Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis

Here we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while showing restrained spatial distribution in lungs and diminished lung inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates coronavirus adaptation and reveal that intrinsic SARS-CoV-2 variant traits shape tropism, immunity, and pathogenesis across hosts. HIGHLIGHTSO_LIIFITM3 is a critical barrier to SARS-CoV-2 adaptation in new host species C_LIO_LIMouse-adapted SARS-CoV-2 strains enable comparative pathology C_LIO_LIOmicron favors nose and large airways, leading to mild lung pathology C_LIO_LIBeta exhibits broad lung replication, driving severe inflammation and dysfunction C_LI

immunology↗

bioRxiv2023

Innate immune control of influenza virus interspecies adaptation

Influenza virus pandemics are caused by viruses from animal reservoirs that adapt to efficiently infect and replicate in human hosts. Here, we investigated whether Interferon-Induced Transmembrane Protein 3 (IFITM3), a host antiviral factor with known human deficiencies, plays a role in interspecies virus infection and adaptation. We found that IFITM3-deficient mice and human cells could be infected with low doses of avian influenza viruses that failed to infect WT counterparts, identifying a new role for IFITM3 in controlling the minimum infectious viral dose threshold. Remarkably, influenza viruses passaged through Ifitm3-/- mice exhibited enhanced host adaptation, a result that was distinct from passaging in mice deficient for interferon signaling, which caused virus attenuation. Our data demonstrate that IFITM3 deficiency uniquely facilitates zoonotic influenza virus infections and subsequent adaptation, implicating IFITM3 deficiencies in the human population as a vulnerability for emergence of new pandemic viruses.

microbiology↗